Circulating Endothelin-1 Levels Increase During Euglycemic, Hyperinsulinemic Clamp in Lean NIDDM Men

OBJECTIVE: To evaluate whether or not insulin stimulates endothelin (ET)-1 secretion in vivo. RESEARCH DESIGN AND METHODS: Plasma ET-1 levels were evaluated in 16 lean normotensive men with non-insulin-dependent diabetes mellitus (NIDDM) (mean age 50.3 +/- 4.1 years) during either a 2-h euglycemic hyperinsulinemic clamp (40 mU insulin.m-2.min-1) or placebo infusion (50 ml isotonic saline) according to a single-blind randomized crossover protocol. RESULTS: Circulating ET-1 levels increased during the euglycemic hyperinsulinemic clamp (from 0.88 +/- 0.38 pg/ml at time 0 to 1.66 +/- 0.22 pg/ml and 1.89 +/- 0.99 pg/ml at 60 and 120 min, respectively P < 0.05 vs. time 0) and returned to baseline levels after the discontinuation of insulin infusion (0.71 +/- 0.22 pg/ml after a 30-min period of recovery NS). Compared with placebo, the euglycemic hyperinsulinemic clamp induced a significant increase in plasma ET-1 levels at 60 min (P < 0.0001) and 120 min (P < 0.0001). Changes in basal insulin levels and corresponding changes in circulating ET-1 levels after a 2-h euglycemic hyperinsulinemic clamp were significantly correlated (r = 0.771, P < 0.0001). A possible unfavorable effect of ET-1 on the tissue sensitivity to insulin-stimulated glucose uptake was suggested by the presence of a negative correlation between total glucose uptake and baseline ET-1 levels (r = -0.498, P < 0.05). CONCLUSIONS: Our findings indicate that circulating ET-1 levels significantly increase during euglycemic hyperinsulinemic clamp in men with NIDDM. The negative correlation between total glucose uptake and circulating ET-1 levels suggests that the peptide might exert negative effects on the insulin sensitivity of target tissues. The consequent increase in insulin secretion as well as the insulin-related ET-1 release from endothelial cells could favor the development of diabetes-related vascular lesions.